tbuckley/cabot-search huggingface dataset:
Association of Primary Versus Rotating Nephrologist Model of Care in Hemodialysis Programs with Patient Outcomes
Authors: Kevin Yau, Nivethika Jeyakumar, Yuguang Kang, Stephanie N. Dixon, Megan Freeman, Amit X. Garg, Ziv Harel, Manish M. Sood, Alison Thomas, Ron Wald, Samuel A. Silver
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Nephrologist staffing models for patients receiving hemodialysis vary widely. Patients may be cared for continuously by a single primary nephrologist or by a group of nephrologists on a rotating basis. It remains unclear whether these differing care models influence clinical outcomes. In this population-based cohort study of more than 14,000 incident patients on maintenance hemodialysis from Ontario, Canada, we found no difference in mortality, kidney transplantation, home dialysis initiation, hospitalizations, or emergency department visits when care was provided by a single primary nephrologist or a rotating group of nephrologists. These results suggest that primary nephrologist models do not necessarily improve objective clinical outcomes, providing reassurance to patients, providers, and administrators that both models are acceptable options.
Safety of guselkumab treatment for up to 5 years in patients with moderate-to-severe psoriasis: pooled analyses across seven clinical trials with more than 8600 patient-years of exposure
Authors: Mark G Lebwohl, Joseph F Merola, Katelyn Rowland, Megan Miller, Ya-Wen Yang, Jenny Yu, Yin You, Daphne Chan, Diamant Thaçi, Richard G Langley
Journal: British Journal of Dermatology (2023)

Abstract Background Guselkumab has demonstrated favourable safety and efficacy across individual clinical studies in adults with moderate-to-severe plaque psoriasis. Objectives To evaluate the safety of guselkumab in patients with psoriasis using pooled data from seven phase II/III studies (X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan registration). Methods All studies, except NAVIGATE and ECLIPSE (active comparator-controlled only), included a 16-week placebo-controlled period; X-PLORE, VOYAGE 1 and VOYAGE 2 included both placebo and active controls. In most studies, guselkumab-treated patients received 100-mg subcutaneous injections at week 0, week 4, and then every 8 weeks thereafter. Safety data were summarized for the placebo-controlled period (weeks 0–16) and through the end of the reporting period (up to 5 years). Incidence rates of key safety events were integrated post hoc, adjusted for the duration of follow-up and reported per 100 patient-years (PY). Results During the placebo-controlled period, 544 patients received placebo (165 PY) and 1220 received guselkumab (378 PY). Through the end of the reporting period, 2891 guselkumab-treated patients contributed 8662 PY of follow-up. During the placebo-controlled period, in the guselkumab and placebo groups, respectively, rates of adverse events (AEs) were 346/100 PY and 341/100 PY, and infections were 95.9/100 PY and 83.6/100 PY. Rates of serious AEs (6.3/100 PY vs. 6.7/100 PY), AEs leading to discontinuation (5.0/100 PY vs. 9.7/100 PY), serious infections (1.1/100 PY vs. 1.2/100 PY), malignancy (0.5 patients/100 PY vs. 0.0 patients/100 PY) and major adverse cardiovascular events (MACE; 0.3/100 PY vs. 0.0/100 PY) were low and comparable between guselkumab and placebo. Through the end of the reporting period, safety event rates were lower than or comparable to the placebo-controlled period in guselkumab-treated patients: AEs, 169/100 PY; infections, 65.9/100 PY; serious AEs, 5.3/100 PY; AEs leading to discontinuation, 1.6/100 PY; serious infections, 0.9/100 PY; malignancy, 0.7/100 PY; and MACE, 0.3/100 PY. There were no cases of Crohn disease, ulcerative colitis, opportunistic infection or active tuberculosis related to guselkumab. Conclusions In this comprehensive analysis of 2891 guselkumab-treated patients with psoriasis followed for up to 5 years (8662 PY), guselkumab demonstrated favourable safety, consistent with previous reports. Safety event rates in guselkumab-treated patients were similar to those observed with placebo and were consistent throughout long-term treatment.
Thrombopoietin-Dependent Myelo-Megakaryopoiesis Fuels Thromboinflammation and Worsens Antibody-Mediated Chronic Renal Microvascular Injury
Authors: Mélodie Douté, Aurélie Sannier, Guillaume Even, Thi-Thu Tran, Ahn-Tu Gaston, Sandrine Delbosc, Stéphane Loyau, Patrick Bruneval, Véronique Witko-Sarsat, Luc Mouthon, Antonino Nicoletti, Giuseppina Caligiuri, Marc Clement
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Kidney-derived thrombopoietin (TPO) increases myeloid cell and platelet production during antibody-mediated chronic kidney disease (AMCKD) in a mouse model, exacerbating chronic thromobinflammation in microvessels. The effect is mirrored in patients with extracapillary glomerulonephritis associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases. Background Chronic thromboinflammation provokes microvascular alterations and rarefaction, promoting organ dysfunction in individuals with various life-threatening diseases. Hematopoietic growth factors (HGFs) released by the affected organ may sustain emergency hematopoiesis and fuel the thromboinflammatory process. Methods Using a murine model of antibody-mediated chronic kidney disease (AMCKD) and pharmacological interventions, we comprehensively monitored the response to injury in the circulating blood, urine, bone marrow, and kidney. Results Experimental AMCKD was associated with chronic thromboinflammation and the production of HGFs, especially thrombopoietin (TPO), by the injured kidney, which stimulated and skewed hematopoiesis toward myelo-megakaryopoiesis. AMCKD was characterized by vascular and kidney dysfunction, TGF β -dependent glomerulosclerosis, and microvascular rarefaction. In humans, extracapillary glomerulonephritis is associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Analysis of albumin, HGF, and inflammatory cytokine levels in sera from patients with extracapillary glomerulonephritis allowed us to identify treatment responders. Strikingly, TPO neutralization in the experimental AMCKD model normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. Conclusion TPO-skewed hematopoiesis exacerbates chronic thromboinflammation in microvessels and worsens AMCKD. TPO is both a relevant biomarker and a promising therapeutic target in humans with CKD and other chronic thromboinflammatory diseases.
Efanesoctocog Alfa: First Approval
Authors: Susan J. Keam
Journal: Drugs (2023)

Efanesoctocog alfa (ALTUVIIIOTM; [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl]), a von Willebrand factor (VWF) independent, recombinant DNA-derived Factor VIII (FVIII) concentrate, has been developed by Bioverativ Therapeutics, Inc (a Sanofi company) and Swedish Orphan Biovitrum AB (Sobi). Efanesoctocog alfa was approved in February 2023 in the USA for use in adults and children with hemophilia A (congenital FVIII deficiency) for: routine prophylaxis to reduce the frequency of bleeding episodes; on-demand treatment and control of bleeding episodes; perioperative management of bleeding. This article summarizes the milestones in the development of efanesoctocog alfa leading to this first approval for hemophilia A.
Creating Safety—The Importance of Providing Psychosocial Support for Refugee Children and Adolescents After Resettlement
Authors: Jana Katharina Denkinger, Florian Junne, Rebecca Erschens
Journal: JAMA Network Open (2023)

Lan Guo, PhD; Li Li, MD; Ke Xu, MS; Wanxin Wang, PhD; Yanyan Ni, PhD; Wenyan Li, MS; Jianhua Gong, MD; Ciyong Lu, PhD; Wei-Hong Zhang, PhD
Seasonality of Respiratory Syncytial Virus — United States, 2017–2023
Authors: Sarah Hamid, Amber Winn, Rishika Parikh, Jefferson M. Jones, Meredith McMorrow, Mila M. Prill, Benjamin J. Silk, Heather M. Scobie, Aron J. Hall
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In the United States, respiratory syncytial virus (RSV) infections cause an estimated 58,000-80,000 hospitalizations among children aged <5 years (1,2) and 60,000-160,000 hospitalizations among adults aged ≥65 years each year (3-5). U.S. RSV epidemics typically follow seasonal patterns, peaking in December or January (6,7), but the COVID-19 pandemic disrupted RSV seasonality during 2020-2022 (8). To describe U.S. RSV seasonality during prepandemic and pandemic periods, polymerase chain reaction (PCR) test results reported to the National Respiratory and Enteric Virus Surveillance System (NREVSS)* during July 2017-February 2023 were analyzed. Seasonal RSV epidemics were defined as the weeks during which the percentage of PCR test results that were positive for RSV was ≥3% (9). Nationally, prepandemic seasons (2017-2020) began in October, peaked in December, and ended in April. During 2020-21, the typical winter RSV epidemic did not occur. The 2021-22 season began in May, peaked in July, and ended in January. The 2022-23 season started (June) and peaked (November) later than the 2021-22 season, but earlier than prepandemic seasons. In both prepandemic and pandemic periods, epidemics began earlier in Florida and the Southeast and later in regions further north and west. With several RSV prevention products in development,† ongoing monitoring of RSV circulation can guide the timing of RSV immunoprophylaxis and of clinical trials and postlicensure effectiveness studies. Although the timing of the 2022-23 season suggests that seasonal patterns are returning toward those observed in prepandemic years, clinicians should be aware that off-season RSV circulation might continue.
An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer
Authors: Carlotta Antoniotti, Alessandra Boccaccino, Robert Seitz, Mirella Giordano, Aurélie Catteau, Daniele Rossini, Filippo Pietrantonio, Lisa Salvatore, Kimberly McGregor, Francesca Bergamo, Veronica Conca, Simone Leonetti, Federica Morano, Giorgio Papiani, Emiliano Tamburini, Maria Bensi, Sabina Murgioni, Douglas Teller Ross, Alessandro Passardi, Isabelle Boquet, Tyler J. Nielsen, Jérôme Galon, Matthew Gordon Varga, Brock L. Schweitzer, Chiara Cremolini
Journal: Clinical Cancer Research (2023)

Abstract Purpose: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. Experimental Design: Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg). Results: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup. Conclusions: DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.
Clinical features, etiologies, and outcomes in adult patients with meningoencephalitis requiring intensive care (EURECA): an international prospective multicenter cohort study
Authors: Romain Sonneville, Etienne de Montmollin, Damien Contou, Ricard Ferrer, Mohan Gurjar, Kada Klouche, Benjamine Sarton, Sophie Demeret, Pierre Bailly, Daniel da Silva, Etienne Escudier, Loic Le Guennec, Russel Chabanne, Laurent Argaud, Omar Ben Hadj Salem, Martial Thyrault, Aurélien Frerou, Guillaume Louis, Gennaro De Pascale, Janneke Horn, Raimund Helbok, Guillaume Geri, Fabrice Bruneel, Ignacio Martin-Loeches, Fabio Silvio Taccone, Jan J. De Waele, Stéphane Ruckly, Quentin Staiquly, Giuseppe Citerio, Jean-François Timsit, Manuel Santafe, Roland Smonig, Damien Roux, Guillaume Voiriot, Bertrand Souweine, Keyvan Razazi, Thibault Ducrocq, Patricia Boronat, Nadia Aissaoui, Danielle Reuter, Alain Cariou, Philippe Mateu, Barabara Balandin Moreno, Paula Vera, Estela Val Jordan, François Barbier, Mickael Landais, Jeremy Bourenne, Antoine Marchalot, Mathilde Perrin, Benjamin Sztrympf, Carole Schwebel, Shakti Bedanta Mishra, Patrick Chillet, Maelle Martin, Hugues Georges, Jean-Claude Lacherade, Romaric Larcher, Gregory Papin, David Schnell, Sulekha Saxena, Frank Chemouni, Juliette Audibert, Eric Mariotte, Shidasp Siami, Italo Calamai, Cédric Bruel, Alexandre Massri, Jesus Priego, Xavier Souloy, Pascal Beuret, Bikram Kumar Gupta, Thomas Ritzenthaler, Sami Hraiech, Aguila Radjou, M. K. Renuka
Journal: Intensive Care Medicine (2023)
Update on Vaccine-Derived Poliovirus Outbreaks — Worldwide, January 2021–December 2022
Authors: John Paul Bigouette, Elizabeth Henderson, Mohamed A. Traoré, Steven G. F. Wassilak, Jaume Jorba, Frank Mahoney, Omotayo Bolu, Ousmane M. Diop, Cara C. Burns
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Circulating vaccine-derived poliovirus (cVDPV) outbreaks* can occur when oral poliovirus vaccine (OPV, containing one or more Sabin-strain serotypes 1, 2, and 3) strains undergo prolonged circulation in under-vaccinated populations, resulting in genetically reverted neurovirulent virus (1,2). Following declaration of the eradication of wild poliovirus type 2 in 2015 and the global synchronized switch from trivalent OPV (tOPV, containing Sabin-strain types 1, 2, and 3) to bivalent OPV (bOPV, containing types 1 and 3 only) for routine immunization activities† in April 2016 (3), cVDPV type 2 (cVDPV2) outbreaks have been reported worldwide (4). During 2016-2020, immunization responses to cVDPV2 outbreaks required use of Sabin-strain monovalent OPV2, but new VDPV2 emergences could occur if campaigns did not reach a sufficiently high proportion of children. Novel oral poliovirus vaccine type 2 (nOPV2), a more genetically stable vaccine than Sabin OPV2, was developed to address the risk for reversion to neurovirulence and became available in 2021. Because of the predominant use of nOPV2 during the reporting period, supply replenishment has frequently been insufficient for prompt response campaigns (5). This report describes global cVDPV outbreaks during January 2021-December 2022 (as of February 14, 2023) and updates previous reports (4). During 2021-2022, there were 88 active cVDPV outbreaks, including 76 (86%) caused by cVDPV2. cVDPV outbreaks affected 46 countries, 17 (37%) of which reported their first post-switch cVDPV2 outbreak. The total number of paralytic cVDPV cases during 2020-2022 decreased by 36%, from 1,117 to 715; however, the proportion of all cVDPV cases that were caused by cVDPV type 1 (cVDPV1) increased from 3% in 2020 to 18% in 2022, including the occurrence of cocirculating cVDPV1 and cVDPV2 outbreaks in two countries. The increased proportion of cVDPV1 cases follows a substantial decrease in global routine immunization coverage and suspension of preventive immunization campaigns during the COVID-19 pandemic (2020-2022) (6); outbreak responses in some countries were also suboptimal. Improving routine immunization coverage, strengthening poliovirus surveillance, and conducting timely and high-quality supplementary immunization activities (SIAs) in response to cVDPV outbreaks are needed to interrupt cVDPV transmission and reach the goal of no cVDPV isolations in 2024.
ASO silencing of a glycosyltransferase, Poglut1, improves the liver phenotypes in mouse models of Alagille syndrome
Authors: Nima Niknejad, Duncan Fox, Jennifer L. Burwinkel, Neda Zarrin-Khameh, Soomin Cho, Armand Soriano, Ashley E. Cast, Mario F. Lopez, Kari A. Huppert, Frank Rigo, Stacey S. Huppert, Paymaan Jafar-Nejad, Hamed Jafar-Nejad
Journal: Hepatology (2023)

Background and Aims: Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in several mouse models generated by removing one copy of Jag1 in the germline with or without reducing the gene dosage of sex-determining region Y-box 9 in the liver. Approach and Results: Using an ASO established in this study, we show that reducing Poglut1 levels in postnatal livers of ALGS mouse models with moderate to profound biliary abnormalities can significantly improve BD development and biliary tree formation. Importantly, ASO injections prevent liver damage in these models without adverse effects. Furthermore, ASO-mediated Poglut1 knockdown improves biliary tree formation in a different mouse model with no Jag1 mutations. Cell-based signaling assays indicate that reducing POGLUT1 levels or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein level and JAG1-mediated signaling, suggesting a likely mechanism for the observed in vivo rescue. Conclusions: Our preclinical studies establish ASO-mediated POGLUT1 knockdown as a potential therapeutic strategy for ALGS liver disease and possibly other diseases associated with BD paucity.
A survey on antimicrobial resistance genes of frequently used probiotic bacteria, 1901 to 2022
Authors: Adrienn Gréta Tóth, Maura Fiona Judge, Sára Ágnes Nagy, Márton Papp, Norbert Solymosi
Journal: Eurosurveillance (2023)

BackgroundAntimicrobial resistance (AMR) is caused by AMR determinants, mainly genes (ARGs) in the bacterial genome. Bacteriophages, integrative mobile genetic elements (iMGEs) or plasmids can allow ARGs to be exchanged among bacteria by horizontal gene transfer (HGT). Bacteria, including bacteria with ARGs, can be found in food. Thus, it is conceivable that in the gastrointestinal tract, bacteria from the gut flora could take up ARGs from food.AimThe study objective was to gain insight into the ARG set carried by commonly used probiotic bacteria that may enter the human body with non-fermented foods, fermented foods, or probiotic dietary supplements (FFPs) and to assess ARG mobility.MethodsNext generation sequencing whole genome data from 579 isolates of 12 commonly employed probiotic bacterial species were collected from a public repository. Using bioinformatical tools, ARGs were analysed and linkage with mobile genetic elements assessed.ResultsResistance genes were found in eight bacterial species. The ratios of ARG positive/negative samples per species were: Bifidobacterium animalis (65/0), Lactiplantibacillus plantarum (18/194), Lactobacillus delbrueckii (1/40), Lactobacillus helveticus (2/64), Lactococcus lactis (74/5), Leucoconstoc mesenteroides (4/8), Levilactobacillus brevis (1/46), Streptococcus thermophilus (4/19). In 66% (112/169) of the ARG-positive samples, at least one ARG could be linked to plasmids or iMGEs. No bacteriophage-linked ARGs were found.ConclusionThe finding of potentially mobile ARGs in probiotic strains for human consumption raises awareness of a possibility of ARG HGT in the gastrointestinal tract. In addition to existing recommendations, screening FFP bacterial strains for ARG content and mobility characteristics might be considered.
Classifying Firearm Injury Using EHR Data—Finding the Phenotype by Reading the Notes
Authors: Roy H. Perlis
Journal: JAMA Network Open (2023)

Erin MacPhaul, MS; Li Zhou, PhD, MS; Stephen J. Mooney, PhD; Deborah Azrael, PhD; Andrew Bowen, BS; Ali Rowhani-Rahbar, MD, PhD; Ravali Yenduri, MPH; Catherine Barber, MPA; Eric Goralnick, MD; Matthew Miller, MD, MPH, ScD
Evaluating Chemical Mixtures in Epidemiological Studies to Inform Regulatory Decisions
Authors: David A. Savitz, Anne M. Hattersley
Journal: Environmental Health Perspectives (2023)

Background: Epidemiological studies are increasingly going beyond the evaluation of health effects of individual chemicals to consider chemical mixtures. To our knowledge, the advantages and disadvantages of addressing chemical mixtures for informing regulatory decisions—as opposed to obtaining a more comprehensive understanding of etiology—has not been carefully considered. Objectives: We offer a framework for the study of chemical mixtures in epidemiological research intended to inform regulatory decisions. We identify a) the different ways mixtures originate (product source, pollution source, shared mode of action, or shared effect on health outcome), b) the use of indicator chemicals to address mixtures, and c) the requirements for epidemiological studies to be informative for regulatory purposes. Discussion: The principal advantage of considering mixtures is to obtain a more complete understanding of the role of the chemical environment as a determinant of health. Incorporating other exposures may improve the assessment of the net effect of the chemicals of interest. However, the increased complexity and potential loss of generalizability may limit the value of studies of mixtures, especially for mixtures based on mode of action or shared health outcomes. Our recommended strategy is to successively assess the marginal contribution of individual chemicals, joint effects with other specific chemicals, and hypothesis-driven evaluation of mixtures rather than applying hypothesis-free data exploration methods. Although more ambitious statistical approaches to mixtures may, in time, be helpful for guiding regulation, the authors believe conventional methods for assessing individual and combined effects of chemicals remain preferable. https://doi.org/10.1289/EHP11899
Evaluating External Validity of Oncology Biosimilar Safety Studies
Authors: Gregory S. Calip, Ivy P. Altomare, Jenny S. Guadamuz
Journal: JAMA Network Open (2023)

Xavier Pivot, MD, PhD; Javier Cortés, MD; Diana Lüftner, MD; Gary H. Lyman, MD; Giuseppe Curigliano, MD; Igor M. Bondarenko, MD; Jin-Hee Ahn, MD; Seock-Ah Im, MD; Maria Litwiniuk, MD; Yaroslav V. Shparyk, MD; Gwo Fuang Ho, MD; Nikolay V. Kislov, MD; Marek Wojtukiewicz, MD; Tomasz Sarosiek, MD; Yee Soo Chae, MD; Jin Seok Ahn, MD; Hyerin Jang, DVM; Sujung Kim, BS; Jiwon Lee, MS; YeChan Yoon, PharmD